dbSNP rs794726869: MARS2:p.Gln184* (chr2-197705955-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_138395.4(MARS2):c.550C>T(p.Gln184*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MARS2
NM_138395.4 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.0880

Publications

2 publications found

Variant links:

Genes affected

MARS2 (HGNC:25133): (methionyl-tRNA synthetase 2, mitochondrial) This gene produces a mitochondrial methionyl-tRNA synthetase protein that is encoded by the nuclear genome and imported to the mitochondrion. This protein likely functions as a monomer and is predicted to localize to the mitochondrial matrix. Mutations in this gene are associated with the autosomal recessive neurodegenerative disease spastic ataxia-3 (SPAX3). [provided by RefSeq, Apr 2014]

MARS2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
spastic ataxia 3
Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
combined oxidative phosphorylation defect type 25
Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

MARS2 links:

ENSG00000222017 (HGNC:):

ENSG00000222017 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-197705955-C-T is Pathogenic according to our data. Variant chr2-197705955-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 193027.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARS2	NM_138395.4 link	c.550C>T	p.Gln184*	stop_gained	Exon 1 of 1	ENST00000282276.8	NP_612404.1	Q96GW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MARS2	ENST00000282276.8 link	c.550C>T	p.Gln184*	stop_gained	Exon 1 of 1	6	NM_138395.4	ENSP00000282276.6	Q96GW9
ENSG00000222017	ENST00000409845.1 link	n.166+7091C>T		intron_variant	Intron 2 of 3	1
ENSG00000222017	ENST00000721462.1 link	n.213+65454C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000132

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 25

Pathogenic:1

Jun 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Benign

0.92

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.074

PhyloP100

0.088

Vest4

0.18

GERP RS

-6.3

Mutation Taster

=16/184

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over